Proton MR Spectroscopy and Diffusion MR Imaging Monitoring to Predict Tumor Response to Interstitial Photodynamic Therapy for Glioblastoma

Abstract

Despite recent progress in conventional therapeutic approaches, the vast majority of glioblastoma recur locally, indicating that a more aggressive local therapy is required. Interstitial photodynamic therapy (iPDT) appears as a very promising and complementary approach to conventional therapies. However, an optimal fractionation scheme for iPDT remains the indispensable requirement. To achieve that major goal, we suggested following iPDT tumor response by a non-invasive imaging monitoring. Nude rats bearing intracranial glioblastoma U87MG xenografts were treated by iPDT, just after intravenous injection of AGuIX® nanoparticles, encapsulating PDT and imaging agents. Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) allowed us an original longitudinal follow-up of post-treatment effects to discriminate early predictive markers. We successfully used conventional MRI, T2 star (T2*), Diffusion Weighted Imaging (DWI) and MRS to extract relevant profiles on tissue cytoarchitectural alterations, local vascular disruption and metabolic information on brain tumor biology, achieving earlier assessment of tumor response. From one day post-iPDT, DWI and MRS allowed us to identify promising markers such as the Apparent Diffusion Coefficient (ADC) values, lipids, choline and myoInositol levels that led us to distinguish iPDT responders from non-responders. All these responses give us warning signs well before the tumor escapes and that the growth would be appreciated.

Ultrasmall AGuIX theranostic nanoparticles for vascular-targeted interstitial photodynamic therapy of glioblastoma

“…25,36 In the present study and in order to maintain the affinity of the DKPPR peptide for NRP-1 recombinant protein, a new functionalization approach has been suggested. It consisted of the conjugation of the KDKPPR peptide moiety to the PS molecules, followed by the grafting of this new PS@peptide conjugate to the surface of the AGuIX NPs through a maleimido-thiol reaction.…”

“…AGuIX particles present primary amines on their surface, and our group has recently published a study in which these groups were used to graft a TPP molecule on AGuIX. 25 In that case, the porphyrin used presented an NHS ester function that could react with an amino group to form a covalent amide bond. In the present study, a new functionalization approach had to be developed in order to maintain the affinity of the KDKPPR peptide for NRP-1 receptor.…”

“…Stereotactic U87 xenograft implantation was performed as previously described in Toussaint et al 25 MRI acquisitions were performed using a small animal 7 Tesla magnet (BioSpec 70/20 USR; Bruker Optik GmbH, Ettlingen, Germany). The most common MRI sequences and T1-weighted imaging (RARE acquisition; relaxation enhancement TR/TE =400/9 ms; matrix: 256×256) were repeated in axial planes before injection and also at different times after AGuIX@PS@KDKPPR intravenous injection (4 µmol⋅kg −1 , porphyrin equivalent) to visualize the tumor tissue in positive signal.…”

“…It was also possible to determine early predictive markers by proton magnetic resonance (MR) spectroscopy and diffusion MRI to discriminate between nonresponding and responding animals. 25 The indirect effects of PDT, including immune response and vascular destruction, are well known to play a major role in photodynamic efficiency. [26][27][28] The latter effect may indirectly initiate a privation of nutrients and molecular oxygen into the tumor tissue.…”

“…Our group recently described such kinds of NPs for iPDT applied to GBM. 25 In this case, 5-(4-carboxyphenyl)-10,15,20-triphenylporphyrin was grafted on the surface of an ultrasmall NP called AGuIX. AGuIX is composed of a polysiloxane core surrounded by DOTA@Gd 3+ complexes (DOTA, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), enabling detection of NPs by magnetic resonance imaging (MRI).…”